Pulmonary fungal infections, such as invasive filamentous pulmonary fungal infection (IFPFI), are major causes of morbidity and mortality in immunocompromised patients. The immune system of an individual may be compromised by some diseases, such as human immunodeficiency acquired immunodeficiency syndrome (AIDS) and systemic lupus erythematosus (SLE), and/or may be deliberately compromised by immunosuppressive therapy. Immunosuppressive therapy is often administered to patients undergoing cancer treatments and/or patients undergoing a transplant procedure. Immunocompromised patients have an increased susceptibility to pulmonary fungal infections. Severely immunocompromised patients, e.g., patients with prolonged neutropenia and patients requiring long-term prednisone therapy, are particularly susceptible to pulmonary and/or nasal fungal infection.
The most common pulmonary fungal infection in immunocompromised patients is pulmonary aspergillosis. Aspergillosis is a disease caused by Aspergillus fungal species (Aspergillus spp.), which invades the body primarily through the lungs. Most commonly, aspergillosis is due to infection with Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, or Aspergillus terreus). Fungal infections of the lung which are caused by Aspergillus include, for example, fungal pneumonia and allergic bronchopulmonary aspergillosis. Other filamentous and dimorphic fungi can lead to pulmonary infections as well. These additional mycotic pathogens are usually endemic and include, for example, blastomycosis, disseminated candidiasis, coccidioidomycosis, paracoccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, and sporotrichosis, pseudallescheriasis, and pneumocsystis carinii. Though typically not affecting the pulmonary system, infections caused by Candida spp., which are usually systemic and most often result from infections via an indwelling device or IV catheter, wound, or a contaminated solid organ transplant, account for 50 to 67% of total fungal infections in immunocompromised patients.
Amphotericin B is the only approved fungicidal compound currently used to treat aspergillosis and is generally delivered intravenously. Amphotericin B is an amphoteric polyene macrolide obtained from a strain of Streptomyces nodosus. In its commercial form, amphotericin B is present in both amorphous and crystalline forms. Amphotericin B formulated with sodium desoxycholate was the first parental amphotericin B preparation to be marketed. Systemic intravenous therapies are constrained by dose-dependent toxicities, such as renal toxicity and hepatotoxicity, which hamper the effectiveness of the treatment and lessen the desirability of prophylactic use of amphotericin B. Even with the approved therapy, aspergillosis incidence is rising and estimated to cause mortality in more than 50% of those infected who receive treatment.
There are numerous additional drawbacks associated with prior formulations and methods for administration of amphotericin B to treat pulmonary infections. For instance, prior efforts to prepare amphotericin B formulations for pulmonary delivery have resulted in formulations exhibiting inadequate delivery efficiency, particularly with respect to delivery to the lung per se. That is, a substantial fraction of the drug was delivered systemically rather than locally, as is desirable in the treatment of a lung infection. Shelf life has also been problematic, as has the dependence of lung deposition on peak inspiratory flow rate.
There remains a need in the art for a safe and effective method and formulation for administering amphotericin B and other antifungal agents, particularly polyene antifungal agents, to the lungs. Ideally, systemic delivery should be minimized while delivery to the affected tissues of the lung should be maximized, and there should not be any significant dependence of the amount of drug delivered to the lungs on inspiratory flow rate. An ideal formulation would also exhibit long-term stability and be administrable using different types of dosage forms and/or delivery devices.